We propose that the in vivo activity of the triphenyethylene type of antiestrogens is mediated by the production of active metabolites which interact with estrogen target tissue receptors. We will test this theory by studying the in vivo metabolism of 3H-(or 14C)-enclomiphene admixed with 14C-(or 3H)-zuclomiphene in rats and hamsters. Metabolites will be isolated and identified from blood, bile and urine. The nature of receptor bound radioactivity will also be determined. The metabolites will be synthesized and tested in vitro and in vivo for biologic activities such as 1) estrogen receptor translocation, replenishment, nuclear retention and processing; 2) induction of progesterone receptor synthesis, ornithine decarboxylase activity and DNA synthesis. These studies should lead to the synthesis of compounds more effective for the treatment of hormone dependent tumors than are the parent "antiestrogen" drugs.